22-cyanohydrins of bis-nor cholen-al compounds



ZZ-CYANDHYDRINS F BIS-NOR CHOLEN-AL CONIPQUNDS Raymond L. Pederson, Kalamazoo Township, Kalamazoo County, and Arnold C. Ott, Kalamazoo, Mich., assignors to The Upjohn Company, Kalamazoo, Mich, a corporation of! Michigan No Drawing. Application (October 10, 1955 Serial No. 539,672

24 Claims. (Cl. 260-45973) The present invention relates to a novel process for the production of 17-ketosteroids and is more particularly concerned with a process of producing 17-ketosteroids selected from the group consisting of 3-oxygenated l7- ketoandrostanes and 17-ketoetiocholanes, the intermediate products 22-cyanohydrins of 3-oxygenated bisnor-17(20)- cholen-22-als and process of production thereof.

The novel process and intermediates may be illustrated by the following equations:

genated in the 3-position, that is substituted by hydroxy,

acyloxy, suitably wherein the acyl group is of an organic carboxylic acid containing from one to eight carbon atoms and preferably of a hydrocarbon caboxylic acid containing from one to eight carbon atoms, inclusive, or keto groups.

In a similar manner 17-ketoetiocholane is used generically and includes 17-ketoetiocholanes which may have double bonds in positions 6(7), 9(11) or the like and Which are preferably oxygenated in position 3, having a 3-hydroxy, acyloxy, as defined above or keto group.

The process of the present invention comprises: treating a bisnor-17(20)-cholen-22-al (I) with hydrogen cyanide or a reagent releasing hydrogen cyanide, for example, an alkali-metal cyanide, a cyanohydrin of a lowermembered ketone in the presence of an acid to obtain atent the corresponding 22-cyanohydrin of the selected bisnor- 17(20)-cholen-22-al and ozonolysing (i. e., treat with ozone at low temperature to obtain an ozonide and decompose the ozonide thus produced, usually by Zinc and acetic acid) the thus prepared cyanohydrin of the 17(20)- bisnorcholen-22-al (II) to obtain the corresponding 17- ketoandrostane or 17-ketoetiocholane (III).

It is an object of the present invention to provide an improved method for the production of l7-ketosteroids of the androstane and etiocholane series from the corresponding 17(20)-bisnorcholane aldehydes, through selective cyanohydrin formation and selective ozonolysis of the l7(20)-double bond. It is another object of the instant invention to produce useful steroid intermediates belonging to the class of ZZ-cyanohydrins of bisnor-17(20)- cholen-22-als without addition of hydrogen cyanide to double bonds or keto groups. Another object of the instant invention is the provision of a process for the production of the ZZ-cyanohydrins of bisnor-17(20)- cholen-ZZ-als, especially the 22-cyanohydrins of 3-ketobisnor-4,17(20)-choladien-22-al, 3-ketobisnor-17(20)-bisnorcholen-ZZ-al, 3-hydroxyand 3-acyloxybisnor-5, 17(20)-choladien-22-als wherein the acyl group is defined as before, and the 6- and ll-hydroxy, acyloxy and keto derivatives thereof, by a selective cyanohydrin formation process. Other objects of the present invention will be apparent to those skilled in the art to which this invention pertains.

The intermediates and the process of the present invention are useful for the production of physiologically active compounds and key-intermediates for the production of such physiologically active compounds. Thus from the cyanohydrin of 3-ketobisnor-4,17(20)-choladien- 22-al, through ozonolysis is obtained 4-androstene-3,17- dione possessing androgenic properties and being an intermediate in the production of testosterone; 3,11-diketobisnor-4,l7(20)-choladien-22-al through its cyanohydrin is useful for the production of androgenic and anabolic active adrenosterone; similarlyz' 3aor 3fi-hydroxybisnorl7(20)-cholen-22-al give anesthetically active 3aor 3 8- hydroXyetiocholan-17 ones, 3,11 diketobisnor 17(20)- cholen-22-al gives etiocholane-3,11,17-trione (general anesthetic activity), 3-hydroxyor 3-acyloXy-6-ketobisnorchloan-22-al provide the corresponding 3-hydroxyetiocholane-6,17-dione and 3-esters thereof which can be oxidized (in case of a 3-ester after hydrolysis) to the corresponding etiocholane-3,6,17-trione (which may be brorninatecl to 4-brornoetiocholane-3,6,17-trione and dehydrobrorninated to give 4-androstene-3,6,17-trione of estrogenic activity). Similarly etiocholane-3,6,17-trione may also be prepared from 3,6-diketobisnor-17(20)- cholen-Zl-al 21-cyanohydrin. 3,1 1-allobisnor-l7(20)- cholen-22-al 22-cyanohydrin yields androgenically active androstane-3,11-17-trione. The cyanohydrins of such 17(20)-bisnorcholenaldehydes are ozonized and give higher yields of 17-ketosteroids than the ozonolysis of the free 17(20)-bisnorcholenaldehydes.

The starting compounds of the present invention are bisnor 17(20) cholen-ZZ-al, such as: bisnor-17-(20)- cholen-ZZ-al, bisnor-4,17(20)-choladien-22-al, 3 -ketobisnor 17(20) cholen-22-al, 3-ketobisnor-4,17(20)-choladien-ZZ-al, 3-hydroXybisnor-17(20)-cholen-22-al, 3aand 3e-acetoxybisnor-17(20)-cholen-22-als, 3aand 3fi-hydroxybisnor-S,17(20) choladien-22-a1s, 3w and Zip-acetoxybisnor-5,17(20)-choladien-22-al, 3,11 diketobisnor- 4, 17 (20) -choladien-22-al, 3-ketoallobisnor- 1 7'( 20 cholen- 22-al, 3,1l-diketoallobisnor-l1(20)-cholen-22-al, 3,6-diketobisnor 17(20) cholen-ZZ-al, 3 ketobisnor-lltx-hydroxyand 3-ketobisnor-115-hydroxy-4,17 (20)-choladien- 22-als, 3/3-hydroxyand 3B-acetoxy-6-ketobisnor-17(20)- cholen-ZZ-als, 3 acetoxyallobisnor-17(20)-cholen-22-al, 3,11-dihydroxybisnor 17 20) cholen-22-al, 3,12-dihy- 3 rex b o 1 cholen 22 at, 3 yloxy isn r- 17( 20) -cholen-22-al, 3-acyloxybisnor-5 17 (2O -choladien- 22-al, 3acyloxy-6-ketobisnor-17(20)-cholen-22-al, 3-acy-loXyhisnorallo-17 (20) -ch olen-22-al, 3-ketobisnor-1 lot-acyloxy 4,l7 (20) choladien-ZZ-al, 3,11 diacyloxybisnor- 17( 20) -cholen-22-al, 3,12-diacyloxybisnor-17(20)-cholen- 22 al, and the like, wherein the acyloxy group is of an organic carboxylic acid containing from one to eight carbon atoms, inclusive, preferably of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive. Representative acyloxy groups illustratively comprise: formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, benzoyloxy, (fi-cyclopentylpropionyloxy), dimethylacetoxy, trimethylacet- QXy, phenylacetoxy, toluyloxy, anisoyloxy, gallyloxy, salicyloyloxy, cinnamyloxy, hemisuccinyloxy, hemitartarylpxy, dihydrogencitryloxy, hemimaleyloxy, hemifumaryloxy, crotonyloxy, acrylyloxy, fl-methylcrotonyloxy, cyclohexanecarbonyloxy, chloroacetoxy, dichloroaceto-xy, trichloroacetoxy, bromoacetoxy, hemiquinolinoyloxy, nicotinyloxy, piperonyloxy, 2-furoyloxy, thioglycollyloxy, para-chlorobenzoyloxy, para-bromobenzoyloxy, metanitrobenzoyloxy, (3,5 -dinitrobenzoyloxy), benzenesulfonyloxy, para-chlorobenzenesulfonyloxy, para-toluenesulfonyloxy, para-nitrobenzenesulfonyloxy, 3,5 -dini tro benzenesulfonyloxy, benzenephosphonyloxy, and the like.

The preparation of the starting compounds belonging to the new class of bisnor-17v(20)-cholen-22-als is described in detail in copending application Serial No. 539,671, filed October 10, 1955,- and comprises: reacting a bisnorcholan aldehyde, either available or produced by reduction of the carboxyl group of the known bisnorcholanic acid to an aldehyde group by methods known in the art EROsenmund, McFayden-Stevens and the more recent method by Weygand et al., Angew. Chem. 65, 525 (1953) with a secondary amine, preferably a cyclic secondary amine such as piperidine, morpholine, pyrrolidine, homomorpholine, and the like, to obtain the corresponding 22- ('N-tertiaryaminobisnor) -20( 22 -cholen, brominating the thus obtained 22-(N-tertiaryaminobis nor)-20(22)-cholene at a temperature between about minus thirty and plus twenty degrees centigrade to obtain a 2 0-bromobisnorcholan-22-al and dehydrobrominating with pyridine or other tertiary amines to obtain the corresponding bisnor-1'fl(20)-cholen-22-al.

In carrying out the process of the present invention the selected bisnor-l7(20)-cho1en-22-al, slur-tied or dissolved in a suitable organic solvent such as methanol, ethanol, dioxane, acetone, tertiary butyl alcohol with methanol or ethanol preferred, is reacted with hydrogen cyanide. The hydrogen cyanide may be suitably introduced as a gas into the solution of the bisnor-l7(20)-cholcn-22-al from a hydrogen cyanide containing gas cylinder or from a hydrogen cyanide producing apparatus, or the hydrogen cyanide may be developed in situ in the reaction vessel by causing an alkali metal cyanide, or a lower keto or aldehyde .cyanohydrin, such as acetone cyanohydrin to react with a dilute acid. In the preferred embodiment of the invention the hydrogen cyanide is produced in situ by adding an alkali metal cyanide such as sodium or potassium cyanide to the solution of the bisnor-17(20)- cho1en-22-al and dropwise thereafter an acid. Strong acid is unnecessary to liberate hydrogen cyanide; organic acids with a melting point lower than zero degrees, preferably lower than fifty degrees centigrade, especially hydrocarbon carboxylic acids such as formic, acetic, propionic, butyric, or the like, or dilute aqueous mineral acids, such as live to ten percent sulfuric, chloric, perchloric acid or the like, are generally employed with acetic acid preferred. Other metal cyanides maybe used instead of the sodium or potassium cyanide, such as lithium cyanide, calcium cyanide, barium cyanide, or the like. In the preferred in situ preparation of the hydrogencyanide gas the rate of addition of the acid is controlled; furthermore the reaction speed is decreased by cooling the reaction mixture to a temperature between minus fifty to zero degrees centigrade. After the reaction is completed the 22-cyanohydrin of the bisnorl7(20)-cho1en-22-al is recovered from the reaction mixture by conventional means preferably by extraction with a water immiscible solvent, such as ether, methylene chloride, chloroform, carbon tetrachloride, benzene, and

the like. In order to obtain the solid ZZ-cyanohydrin of bisnor-17 (20)-cholen-22-a1 the extracts are concentrated until the solid product precipitates. Purification is effected by recrystallization from organic solvents such as ether, methanol, ethanol, dioxane, or the like.

For the purpose of obtaining a 17-ketosteroid selected from 17-ketoandrostanes and 17-ketoeti0cholanes, the cyanohyd'rin of the bisnor-17(20)-cholen-22-a:l is submitted to ozonolysis. For ozonolysis it is not necessary that the cyanohydrin of the bisnor-17 (20)-cho1en 22-al be isolated, in its stead the solution resulting from'the extraction of the reaction mixture can be used. In the preferred embodiment of the instant invention the methylene chloride or'chloroform solution resulting from the extraction of the before-mentioned reaction mixture is concentrated to approximately one millimole ofthe cyanohydrin of the steroid per ten milliliters of solution. Smaller or greater concentration of steroid cyanohydrin may also be used. The thus obtained solution is then cooled to a temperature between minus forty to minus ninety degrees and ozonized with a mixture of ozoneoxygen. The thus obtained ozonide is decomposed in the usual manner with zinc dust and the acetic acid. Stirring is preferred during the decomposition of the ozonide. The product, a 17-ketosteroid, is recovered by conventional means, such as removal of the zinc by filtration and concentrating the reaction mixture to dryness in vacuo.

The thus obtained ketosteroid is purified by conventional procedures, preferably by recrystallization from suitable solvents such as ether, methanol, ethanol, acetone, Skellysolve B hexanes, benzene, and the like.

The following examples are illustrative of the process and products of the present invention but are not to be construed as limiting.

EXAMPLE 1 C yanohydri n of 3 -ket0bisn0r-4 ,1 7 2 0 -ch0 ladien-2 2 al A slurry consisting of 8.16 grams (25 millimoles) of 3.-ketobisnor-4,17(20)-choladien-22-al of melting point 124 to 133 degrees centigrade, 12.3 grams (250 millimoles) of sodium cyanide and 75 milliliters of anhydrous methanol was cooled to minus twenty degrees centigrade and thereto was added under continuous rapid stirring 11.5 milliliters (200 millimoles) of glacial acetic acid during a period of one hour. The mixture during the dropwise addition became very thick and the temperature increased to zero degrees centigrade. Thereafter the reaction mixture was placed in a refrigerator and kept at a temperature between zero and five degrees centigrade for a period of 48 hours. The thus obtained thick paste was shaken with 300-milliliters of ice cold methylene chloride. The resulting mixture was washed with milliliter portions, then with four fifty-milliliter portions of ice water. The methylene chloride solution was dried with ten grams of anhydrous sodium sulfate during a period of eighteen hours at a temperature of zero to five degrees centigrade. The mixture thereupon was filtered and concentrated to 250 millilitersat a temperature of 20 to '25 degrees centigrade and under partially reduced pressure. This solution was ready for the ozonolysis described in Example 2.

Evaporation to dryness of such a solution yielded an amorphous solid which upon recrystallization from absolute ether gave fine white crystals of melting point 178 to 183 degrees centigrade (decomposition).

Mil if 232.5 m E 17,150

REE" 3360 cm.- (OH), 1660 cm.- (conj. C=)

EXAMPLE 2 4-androstene-3J7-dione The 250 milliliters of methylene chloride solution containing theoretically 25 millimoles of the monocyanohydrin of 3-ketobisnor-4,17(20)-choladien-22-al of Example 1, was cooled to about minus seventy degrees centigrade. To this solution was added 2.4 milliliters of anhydrous pyridine and the solution was ozonized with an ozone-oxygen stream producing 0.405 millimole of ozone per minute for a period of 75 minutes. During the last three minutes ozone passed into the overflow trap. The absorption of ozone was 29.4 millimoles or 1.18 moles per mole of steriod. The cold ozonized solution was thereupon quickly transferred to a flask equipped with a stirrer, and fifty milliliters of acetic acid was added in one portion, followed immediately by five grams of zinc dust. The mixture was then stirred rapidly for a period of two hours, during which time it reached room temperature. Thereafter the reaction mixture was filtered and diluted with 250 milliliters of Skellysolve A hexanes. It was thereupon washed with 100 milliliters of Water, then two SO-milliliter portions of water, two lSO-milliliter portions of ten percent sodium hydroxide solution, fifty milliliters of water, fifty milliliters of ten percent hydrochloric acid solution and two SO-milliliter portions of water. Thereafter the solution was dried overnight with anhydrous sodium sulfate at a temperature between zero and five degrees, then filtered and concentrated to dryness in vacuo. The last traces of solvent were removed at sixty degrees centigrade at a pressure of twenty to thirty milliliter mercury leaving 6.55 grams (91.4 percent yield) of white crystals of melting point 155 to 160 degrees of 4-androstene-3,17- dione. (4-androstene-3,17-dione has two crystal forms: one melting at 142 to 144 degrees centigrade, the other at 173 to 174 degrees centigrade.)

' EXAMPLE 3 ZZ-cyanohya'rin of 3a-acet0xybisnor-17(20)-cholen-22-al In the same manner as Example 1, a solution of 30aacetoXybisnor-17(20)-cholen-22-al in ethanol was treated with potassium cyanide and ten percent hydrochloric EXAMPLE 4 3a-acet0xyeti0ch0lan-17-0ne In the manner given in Example 2, 3a-acetoxybisnorl7(20)-cholen-22-al was subjected to ozonolysis, while dissolved in methylene dichloride, to give 3a-acetoxyetiocholan-17-one.

EXAMPLE 5 ZZ-cyanohydrin of 3,11-diketobisn0r-4-17(20) -ch0ladien- 22-al In the manner given in Example 1, reacting 3,1l-diketobisnor-4,17()-choladien-22-al, dissolved in methanol, with sodium cyanide and acetic acid yielded the 22-cyanohydrin of 3,11-diketobisnor-4,17(20)-choladien- 22-al.

EXAMPLE 6 4-andr0stene-3,1 1,17-trione (adrenosterone) Ozonolyzing in the manner shown in Example 2, the 22-cyanohydrin of 3,11-diketobisnor-4,17(20)-choladien- 22-al produced 4-androstene-3,11,17-trione (adrenosteone).

EXAMPLE 7 ZZ-cyamohydrin of 3,6-acet0xy-6-kembisn0r-17(20)- ch0len-22-al In the manner given in Example 1, reacting 3/3-acetoXy-6-ketobisnor-l7(20) cholen 22 a1, dissolved in methanol, with sodium cyanide and acetic acid, yielded the 22-cyanohydrin of 3,8 acetoxy 6 ketobisnor 17 (20)- cholen-22-al.

EXAMPLE 8 3B-acetoxyetioch'0lane-6,17-di0ne Ozonolyzing in the manner shown in Example 2, the 22-cyanohydrin of 3,8-acetoXy-6-ketobisnor-17(20)-cholen-22-al produced 3;.3-acetoXyetiocholane-6,17-dione.

EXAMPLE 9 ZZ-cyzmohydrin of 3,6-diket0bisn0r-l7 (20) -ch0 len-22-al In the manner given in Example 1, reacting 3,6-diketobisnor-17(20)-cholen-22-al, dissolved in methanol, with sodium cyanide and acetic acid, yielded the Z-cyanohydrin of 3,6-diketobisnor-17(20)-cholen-22-al.

sodium cyanide and acetic acid, yielded the 22-cyanohydrin of 3-ketoallobisnor-17(20)-cholen-22-al.

EXAMPLE 12 Andr0stane-3,1 7-di0ne Ozonolyzing in the manner shown in Example 2, the 22-cyanohydrin of 3-ketoallobisnor-17(20)cholen-22-al produced androstane-3-17-dione.

EXAMPLE 13 22-cyanohydrin of 3ot-hydr0xybisn0r-5J7(20)-choladien- 22-al In the manner given in Example 1, reacting 3a-hydroxybisnor-5,l7(20)-choladien 22 al, dissolved in methanol, with sodium cyanide and acetic acid, yielded the 22 -cyanohydrin of 3a-hydroxybisnor-5,l7(20)- choladien-22-al.

EXAMPLE 14 3 a-hydrOxy-S -androsten-l 7 -one Ozonolyzing in the manner shown in Example 2, the 22- cyanohydrin of 3u-hYdIOXYbiS110f-5,17(20)-Ch0l&dl6n- 22-a1 produced 3a-hydroXy-5-androsten-l7-one.

EXAMPLE 15 22-cyanohydrin of 3a-hydroxyallobisnor-l 7 (20 -ch0len- 7 EXAMPLE 16 3a-hydroxyandrostan-1 7-0ne Ozpnolyzing in the manner shown: in Example 2, the 22-cyanohydrin of 3u-hydroxyallobisnor-17(20)-cholen- 22-al produced 3u hydroxyandrostan-17-one.

In the manner given in Example 1, reacting 3ozacetoxyallobisiior 17(20) i cholen-22-al, dissolved in methanol, with sodium cyanide and acetic acid, yielded the ZZ-cyanohydrin of 3m acetoxyallobisnor-ITQO)- cholen-22-al.

EXAMPLE 18 3 a-acetoxyandrostqn-I 7 -one Ozonolyzing in the manner shown in Example 2, the 22-cyanohydrin of 3a-acetoxyallobisnorrl7(20):cholen- 22-al produced 3a-acetoxyandrostan-17-one.

EXAMPLE 19- 22-cyan0hydrin of 3,11-diketbisnor-17(20)-ch0len-22-al.

In the manner given in Example 1, reacting 3,ll-diketobisnor-'17(20)-cholen-22 al, dissolved in methanol, with sodium cyanide and acetic acid, yielded the 22 -.cyanohydrin of 3,11-diketobisnor:17(20)-cholen-22-a1.

EXAMPLE 20 Eti0cholane-3,11,17-trione Ozonolyzing in the manner shown in Example 2, the 22-cyanohydrin of 3,1l-diketobisnor l7(20}-cholen-22fal produced etiocholane-3,11,17-trione.

EXAMPLE 21 of 3-ket0bisno.r-l1u-hydroxy-17(20)- cholen-ZZ-ql V In the manner given in Example 1, reacting 3-ketobisnor 11 hydroxy-l7(20) cholen-22-a1, dissolved in methanol, with sodiurn cyanide and acetic acid, yielded the 2Z-cyanohydrin' of 3-ketobisnor-1la hydroxy- 17.(-20)- cholen-22-al. i

22-cyanohydrin EXAMPLE 22 11m-hydrorygtiocholnne-j,1 7-dione Ozonolyzing in the manner shown in Example 2, the 22-cyanohydrin of 3 -ketobisnor-lla-hydroxy-l7(20)- cholen-22-al produced 11a-hydroxyetiocholane3,I Z-dione.

EXAMPLE 23 ZZ-cyanohydrin of 3-ketobisn 0r- 1lp-hydroxy-l 7(20) cholen-ZZ-al Z-PWnO Yd i 9f 1l ikewa q ima -l7( m-c o s- In the manner given in Example 1, reacting 3,11- diketoallobisnor 17(20) cholen-ZZ-al, dissolved in methanol, with sodium cyanide and acetic acid, yielded the 22-cyanohydrin of 3,11-diketoallobisnor-17(20)- chloen-22-al. V

EXhMPLE 26 Androstane-il 1 ,1 7-tri0ne Ozonolyzing in the manner shown in Example 2, the

22-cyanohydrin of 3,1l-diketoallobisnor-17(20)-cholen- 22-a1 produced androstane-3,11,17-tri0ne.

In the same manner as Example 1, other cyanohydrins may be produced, such' as illustratively the 22-cyanohydrins of 3-ketobisnor-1 1 u-hydroxy-4, 17 2O -cho ladien-22- a1," '3-ltetobisnor 65,1 lot dihydroxy-4,l7(20)-choladien- 22 a], 3,6 diketoallobisnor-l lqt-acetoxy-17(20)-cholen- 22-a], 3-ketobisnorallo-1 1 fi-hydroxy- 17 20 -cholen-2 2-al, 3-ketobi snor-6fll la-dipropionyloxy-4,17(20) choladien- 22-al, 3,12-diketobisnor-4,l7(20)-choladien-22-al, 3,7- dike toallobisnor-U(20) cholen-22-al, and the like.

These ZZ-cyanohydrins can be subjected to ozonolysis in the manner shown in Example 2 to give respectively 1 lu-hydroxyl-androstene-3,17-dione, 65,1 1a -dihydroxy- 4-andro'stene-3 ,17-dione, 11a-acetoxyandrostane-3,6-dione, 11fl-hydroXyandrostane-3,17-dione, 65,1105 dipropionyloxy-4-androstene-3,17-dione, 4-androstene-3,12,17-trione, androstane-3,7,17-t1ione, and the like.

It is to'be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scopeof the appended claims.

We claim:

1. The 2 2 -cyanohydrin of a bisnor-l7(20) -cholen-2 2- a1 substituted in theft-position by a group selected from hydroxy, acyloxy wherein the acyl group is of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive, and keto.

i 2. The 22-cyanohydrin of a 3-ketobisnor-17(20)- cholen-22-al.

3 ZZ-cyahohydrin of 3-ketobisnor-4,17(20)-choladien- 22-al. '4

' 4. 22-cyanohydrin of 3,1l-diketobisnorl,17(20)-choladien-ZZ-al. i

5. ZZ-cyanohydrin of 3,6-diketobisnor-17(20)-cholen- 22-al.

6. The 22-cyanohydrin of a allobisnor-17(20)-cholen- 22-al substituted in the 3-position by a group selected from hydroxy, acyloxy wherein the acyl group is of a hydrocarbon carboxylic acid containing from one to eightcarbqn atom, inclusive, and keto.

7. 22-cyanohydrin of 3-ketoallobisnor-17(20)-cholen- 22-a1.

8. The ZZ-cyanohydrin of a 3-acyloxybisnor-17(20)- cholen-22-al, wherein the acyl group is of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive.

9. ZZ-cyainohydrin of 3a-acetoxyb isnor-17(20)-cholen- 22-al.

10. A process for the production of a 22-cy-anohydrin of a 3-oxygenated bisnor-17(20)-cholen-22-al which comprises: reacting a 3-oxygenated bisnor-l7(20)-cholen- 22- al wherein the 3-oxygenated group is selected from the class consisting of hydroXY, acyloxy, wherein the acyl group is of an organic carboxylic acid containing from one to eight carbon atoms, inclusive, and keto, with hydrogen cyanide to obtain the cyanohydrin of the corresponding B-oi'tygenated bisnor-17(20)-cholen-22eal.

11. A process for the production of a 22-cyanohydrin of a 3-oxygenated bisnor -17(2 0)-cholen-22-al which comprises: adding, to a mixture of a 3-oxygenated bisnor- 17(20)-cholen-22 -al wherein the 3-oxygenated group is selected from the class consisting of hydroxy, acyloxy, wherein the .acyl group is of an organic carboxylic acid containing from one to eight carbon atoms, inclusive, and keto an d an alkali-metal cyanide in an organic solvent, an acid selected from the group consisting of organic carboxylic acids of low melting point and dilute aqueous mineral acids to obtain the 22-cyanohydrin of the 3- oxygenated bisnor-17 20) -cholen-22-al.

12. A process for the production of a ZZ-cyanohydrin of a 3-ketobisnor-17(20)-cholen-22-al which comprises: adding, to a mixture of a 3-ketobisnor-17(20)-cholen-22- al and an alkali-metal cyanide in an organic solvent, an acid selected from the group consisting of organic carboxylic acids of low melting point and dilute aqueous mineral acids to obtain the ZZ-cyanohydrin of the 3-ketobisnor-l7(20)-cholen-22-al.

13. A process for the production of the ZZ-cyanohydrin of 3-ketobisnor-4,17(20)-choladien-22-al which comprises: adding acetic acid at a temperature between about minus fifty and zero degrees centigrade to a mixture of 3-ketobisnor-4,17(20)-choladien-22-al and an alkalimetal cyanide in an organic solvent to obtain the 22- cyanohydrin of 3-ketobisnor-4,l7(20)-choladien-22-al.

14. A process for the production of the 22-cyanohydrin of 3,11-diketbisnor-4,l7(20)-choladien-22-al which comprises: adding acetic acid at a temperature between about minus fifty and about zero degrees centignade to a mixture of 3,1l-diketobisnor-4,l7(20)-ch-oladien-22-al and an alkali-metal cyanide in an organic solvent to obtain the ZZ-cyanohydrin of 3,1l-diketobisnor-4,l7(20)- choladien-ZZ-al.

15. A process for the production of the 22-cyanohydrin of 3,6-diketobisnor-l7(20)-cholen-22-al which comprises: adding acetic acid at a temperature between about minus fifty and about zero degrees centigrade to a mixture of 3,6-diketobisnor-4,17(20)-choladien-22-al and an alkali-metal cyanide in an organic solvent to obtain the ZZ-cyanohydrin of 3,6-diketobisnor-17(20)- cholen-ZZ-al.

16. A process for the production of the 22-cyanohydrin of 3-ketoallobisnor-17(20)-cholen-22-al which comprises: adding acetic acid at a temperature between about minus fifty and about zero degrees centigrade to a mixture of 3-ketoall-obisnor-17(20)-cholen-22-al and an alkali-metal cyanide in an organic solvent to obtain the 22-cyanohydrin of 3-ketoallobisnor-17(20)-cholen-22-al.

17. A process for the production of the 22-cyanohydrin of 3u-acetoxybisnor-17(20)-cholen-22-al which comprises: adding acetic acid at a temperature between about minus fifty and about zero degrees centigrade to a mixture of 3a-acetoxybisnor-17(20)-cholen-22-al and an alkali-metal cyanide in an organic solvent to obtain the ZZ-cyanohydrin of 3u-acetoxybisnor-17(20)-cholen-22-al.

18. A process for the production of a 3-oxygenated 17-ketosteroid selected from the group consisting of 17- ketoandrostanes and 17-ketoetiocholanes, which comprises: reacting a 3-oxygenated bisnor-17(20)-cholen-22- a1 wherein the 3-oxygenated group is selected from the class consisting of hydroxy, acyloxy wherein the acyl group is of an organic carboxylic acid containing from one to eight carbon atoms, inclusive, and keto with hydrogen cyanide to obtain the cyanohydrin of the corresponding 3-oxygenated bisnor-17(20)-cholen-22al and subjecting the thus obtained cyanohydrin to ozonolysis to obtain the corresponding 3-oxygenated 17-ketosteroid.

19. A process for the production of a 3-oxygenated 17-ketosteroid selected from the group consitsing of 17- ketoandrostanes and 17-ketoetiocholanes, which comprises: adding, to a mixture of a 3-oxygenated bisnor- 17(20)-cholen-22-al wherein the 3-oxygenated group is selected from the class consisting of hydroxy, acyloxy, wherein the acyl group is of an organic carboxylic acid containing from one to eight carbon atoms, inclusive, and keto and an alkali-metal cyanide in an organic solvent, an acid selected from the group consisting of organic carboxylic acids of low melting point and dilute aqueous mineral acid to obtain the ZZ-cyanohydrin of the 3- oxygenated bisnor-17(20)-cholen-22-al, and subjecting the thus obtained 3-oxygenated bisnor-l7(20)-cholen-22- al 22-cyanohydrin to ozonolysis to obtain the corresponding 3-oxygenated 17-ketosteroid.

20. A process for the production of 4-androstene- 3,17-dione which comprises: adding acetic acid at a temperature between about minus fifty and about zero degrees centigrade to a mixture of 3-ketobisnor-4,l7(20)- choladien-22-al and an alkali-metal cyanide in an organic solvent to obtain the cyanohydrin of 3-ketobisnor- 4,l7(20)-choladien-22-al and submitting the thus obtained 3-ketobisnor-4,17(20)-choladien-22-al 22-cyan0- hydrin to ozonolysis to obtain 4-andro-stene-3,17-dione.

21. A process for the production of adrenosterone which comprises: adding acetic acid at a temperature between about minus fifty and about zero degrees centigrade to a mixture of 3,1l-diketobisnor-4,17(20)choladien-22-al and an alkali-metal cyanide in an organic solvent to obtain the 22-cyanohydrin of 3,11-diketobisnor- 4,17(20)-choladien-22-al and submitting the thus obtained 3,11 diketobisnor 4,17(20) choladien 22 al 22-cyanohydrin to ozonolysis to obtain adrenosterone.

22. A process for the production of etiocholane- 3,6,17-trione which comprises: adding acetic acid at a temperature between minus fifty and about zero degrees centigrade to a mixture of 3,6-diketobisnor-l7 (20)-cholen- 22-al and an alkali-metal cyanide in an organic solvent to obtain 3,6-diketobisnor-17(20)-cholen-22-al 22-cyanohydrin and subjecting the thus produced 3,6-diketobisnor- 17(20)-cholen-22-al 22-cyanohydrin to ozonolysis to obtain etiocholan-3,6,17-trione.

23. A process for the production of androstane-3,17- dione which comprises: adding acetic acid at a temperature between about minus fifty and about zero degrees centigrade to a mixture of 3-ketoallobisnor-17(20)- cholen-22-al and an alkali-metal cyanide in an organic solvent to obtain the 22-cyanohydrin of 3-ketoallo-bisnorl7(20)-cholen-22-al and subjecting thus obtained 3-ketobisnor 4,17(20) choladien 22 al 22 cyanohydrin to ozonolysis to obtain androstane-3,17-dione.

24. A process for the production of 3a-acetoxyetiocholan-17-one which comprises: adding acetic acid at a temperature between about minus fifty and about zero degrees centigrade to a mixture of 3u-acetoxybisnor- 17(20)-cholen-22-al and an alkali-metal cyanide in an organic solvent to obtain the 22-cyanohydrin of 3a-aoetoxybisnor-17(20)-cholen-22-a1 and subjecting the thus obtained 3a-acetoxybisnor-l7(20)-cholen-22-al 22-cyanohydrin to ozonolysis to obtain 3u-acetoxyetiocholan-17- one.

References Cited in the file of this patent UNITED STATES PATENTS 2,541,104 Sarett Feb. 13, 1951 

1. THE 22-CYANOHYDRIN OF A BISNOR-17(20)-CHOLEN-22AL SUBSTUTUTED IN THE 3-POSITION BY A GROUP SELECTED FROM HYDROXY, ACTLOXY WHEREIN THE ARCYL GROUP IS OF A HYDROCARBON CARBOXYLIC ACID CONTAINING FROM ONE TO EIGHT CARBON ATOMS, INCLUSIVE, AND KETO.
 18. A PROCESS FOR THE PRODUCTION OF A 3-OXYGENATED 17-KETOSTEROID SELECTED FROM THE GROUP CONSISTING OF 17KETOANDROSTANES AND 17-KETOETIOCHOLANES, WHICH COMPRISES: REACTING A 3-OXYGENERATED BISNOR-17(20)-CHOLEN-22AL WHEREIN THE 3-OXYGENATED GROUP IS SELECTED FROM THE CLASS CONSISTING OF HYDROXY, ACYLOXY WHEREIN THE ACYL GROUP IS OF AN ORGANIC CARBOXYLIC ACID CONTAINING FROM ONE TO EIGHT CARBON ATOMS, INCLUSIVE, AND KETO WITH HYDROGEN CYANIDE TO OBTAIN THE CANOHYDRIN OF THE CORRESPONDING 3-OXYGENATED BISNOR-17(20)-CHOLEN-22-AL AND SUBJECTING THE THUS OBTAINED CYANOHYDRIN TO OZONOLYSIS TO OBTAIN THE CORRESPONDING 3-OXYGENATED 17-KETOSTEROID. 